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LGMDD1 natural history and phenotypic spectrum: Implications for clinical trials
OBJECTIVE: To delineate the full phenotypic spectrum and characterize the natural history of limb girdle muscular dystrophy type D1 (LGMDD1). METHODS: We extracted age at clinical events of interest contributing to LGMDD1 disease burden via a systematic literature and chart review. Manual muscle tes...
Autores principales: | , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
John Wiley and Sons Inc.
2022
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9930420/ https://www.ncbi.nlm.nih.gov/pubmed/36427278 http://dx.doi.org/10.1002/acn3.51709 |
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author | Findlay, Andrew R. Robinson, Sarah E. Poelker, Stephanie Seiffert, Michelle Bengoechea, Rocio Weihl, Conrad C. |
author_facet | Findlay, Andrew R. Robinson, Sarah E. Poelker, Stephanie Seiffert, Michelle Bengoechea, Rocio Weihl, Conrad C. |
author_sort | Findlay, Andrew R. |
collection | PubMed |
description | OBJECTIVE: To delineate the full phenotypic spectrum and characterize the natural history of limb girdle muscular dystrophy type D1 (LGMDD1). METHODS: We extracted age at clinical events of interest contributing to LGMDD1 disease burden via a systematic literature and chart review. Manual muscle testing and quantitative dynamometry data were used to estimate annualized rates of change. We also conducted a cross‐sectional observational study using previously validated patient‐reported outcome assessments (ACTIVLIM, PROMIS‐57) and a new LGMDD1 questionnaire. Some individuals underwent repeat ACTIVLIM and LGMDD1 questionnaire assessments at 1.5 and 2.5 years. RESULTS: A total of 122 LGMDD1 patients were included from 14 different countries. We identified two new variants (p.E54K, p.V99A). In vitro assays and segregation support their pathogenicity. The mean onset age was 29.7 years. Genotype appears to impact onset age, weakness pattern, and median time to loss of ambulation (34 years). Dysphagia was the most frequent abnormality (51.4%). Deltoids, biceps, grip, iliopsoas, and hamstrings strength decreased by (0.5‐1 lb/year). Cross‐sectional ACTIVLIM and LGMDD1 questionnaire scores correlated with years from disease onset. Longitudinally, only the LGMDD1 questionnaire detected significant progression at both 1.5 and 2.5 years. Treatment trials would require 62 (1.5 years) or 30 (2.5 years) patients to detect a 70% reduction in the progression of the LGMDD1 questionnaire. INTERPRETATION: This study is the largest description of LGMDD1 patients to date and highlights potential genotype‐dependent differences that need to be verified prospectively. Future clinical trials will need to account for variability in these key phenotypic features when selecting outcome measures and enrolling patients. |
format | Online Article Text |
id | pubmed-9930420 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | John Wiley and Sons Inc. |
record_format | MEDLINE/PubMed |
spelling | pubmed-99304202023-02-16 LGMDD1 natural history and phenotypic spectrum: Implications for clinical trials Findlay, Andrew R. Robinson, Sarah E. Poelker, Stephanie Seiffert, Michelle Bengoechea, Rocio Weihl, Conrad C. Ann Clin Transl Neurol Research Articles OBJECTIVE: To delineate the full phenotypic spectrum and characterize the natural history of limb girdle muscular dystrophy type D1 (LGMDD1). METHODS: We extracted age at clinical events of interest contributing to LGMDD1 disease burden via a systematic literature and chart review. Manual muscle testing and quantitative dynamometry data were used to estimate annualized rates of change. We also conducted a cross‐sectional observational study using previously validated patient‐reported outcome assessments (ACTIVLIM, PROMIS‐57) and a new LGMDD1 questionnaire. Some individuals underwent repeat ACTIVLIM and LGMDD1 questionnaire assessments at 1.5 and 2.5 years. RESULTS: A total of 122 LGMDD1 patients were included from 14 different countries. We identified two new variants (p.E54K, p.V99A). In vitro assays and segregation support their pathogenicity. The mean onset age was 29.7 years. Genotype appears to impact onset age, weakness pattern, and median time to loss of ambulation (34 years). Dysphagia was the most frequent abnormality (51.4%). Deltoids, biceps, grip, iliopsoas, and hamstrings strength decreased by (0.5‐1 lb/year). Cross‐sectional ACTIVLIM and LGMDD1 questionnaire scores correlated with years from disease onset. Longitudinally, only the LGMDD1 questionnaire detected significant progression at both 1.5 and 2.5 years. Treatment trials would require 62 (1.5 years) or 30 (2.5 years) patients to detect a 70% reduction in the progression of the LGMDD1 questionnaire. INTERPRETATION: This study is the largest description of LGMDD1 patients to date and highlights potential genotype‐dependent differences that need to be verified prospectively. Future clinical trials will need to account for variability in these key phenotypic features when selecting outcome measures and enrolling patients. John Wiley and Sons Inc. 2022-11-25 /pmc/articles/PMC9930420/ /pubmed/36427278 http://dx.doi.org/10.1002/acn3.51709 Text en © 2022 The Authors. Annals of Clinical and Translational Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association. https://creativecommons.org/licenses/by-nc-nd/4.0/This is an open access article under the terms of the http://creativecommons.org/licenses/by-nc-nd/4.0/ (https://creativecommons.org/licenses/by-nc-nd/4.0/) License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non‐commercial and no modifications or adaptations are made. |
spellingShingle | Research Articles Findlay, Andrew R. Robinson, Sarah E. Poelker, Stephanie Seiffert, Michelle Bengoechea, Rocio Weihl, Conrad C. LGMDD1 natural history and phenotypic spectrum: Implications for clinical trials |
title |
LGMDD1 natural history and phenotypic spectrum: Implications for clinical trials |
title_full |
LGMDD1 natural history and phenotypic spectrum: Implications for clinical trials |
title_fullStr |
LGMDD1 natural history and phenotypic spectrum: Implications for clinical trials |
title_full_unstemmed |
LGMDD1 natural history and phenotypic spectrum: Implications for clinical trials |
title_short |
LGMDD1 natural history and phenotypic spectrum: Implications for clinical trials |
title_sort | lgmdd1 natural history and phenotypic spectrum: implications for clinical trials |
topic | Research Articles |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9930420/ https://www.ncbi.nlm.nih.gov/pubmed/36427278 http://dx.doi.org/10.1002/acn3.51709 |
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